chr22-29330406-C-T

Position:

chr22-29330406-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

The NM_001127.4(AP1B1):c.2738G>A(p.Arg913Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00173 in 1,613,628 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 2 hom. )

Consequence

AP1B1
NM_001127.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 6.14

Variant links:

Genes affected

AP1B1 (HGNC:554): (adaptor related protein complex 1 subunit beta 1) Adaptor protein complex 1 is found at the cytoplasmic face of coated vesicles located at the Golgi complex, where it mediates both the recruitment of clathrin to the membrane and the recognition of sorting signals within the cytosolic tails of transmembrane receptors. This complex is a heterotetramer composed of two large, one medium, and one small adaptin subunit. The protein encoded by this gene serves as one of the large subunits of this complex and is a member of the adaptin protein family. This gene is a candidate meningioma gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

AP1B1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AP1B1. . Gene score misZ 3.1177 (greater than the threshold 3.09). Trascript score misZ 3.2098 (greater than threshold 3.09). GenCC has associacion of gene with MEDNIK syndrome, ichthyosiform erythroderma, corneal involvement, and hearing loss.

BP4

Computational evidence support a benign effect (MetaRNN=0.020324826).

BP6

Variant 22-29330406-C-T is Benign according to our data. Variant chr22-29330406-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3039348.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00114 (173/152346) while in subpopulation NFE AF= 0.00178 (121/68028). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP1B1	NM_001127.4 linkuse as main transcript	c.2738G>A	p.Arg913Gln	missense_variant	21/23	ENST00000357586.7	NP_001118.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP1B1	ENST00000357586.7 linkuse as main transcript	c.2738G>A	p.Arg913Gln	missense_variant	21/23	1	NM_001127.4	ENSP00000350199	P4	Q10567-1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.0209

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00178

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00130

AC:

325

AN:

250728

Hom.:

AF XY:

0.00144

AC XY:

195

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00179

AC:

2612

AN:

1461282

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

1213

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.000245

Gnomad4 NFE exome

AF:

0.00216

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152346

Hom.:

Cov.:

AF XY:

0.000966

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00178

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00167

Hom.:

Bravo

AF:

0.00119

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00150

AC:

182

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00160

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

AP1B1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.0053

Eigen_PC

Benign

0.040

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.019

MetaRNN

Benign

0.020

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.67

N;N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.063

T;T;T;T;T;T

Sift4G

Benign

0.55

T;T;T;T;T;T

Vest4

0.79

MVP

0.44

MPC

0.70

ClinPred

0.021

GERP RS

4.4

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over